Hanai Y, Tokuda H, Takai S, Harada A, Ohta T, Kozawa O
Department of Pharmacology, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan.
Horm Metab Res. 2006 Mar;38(3):152-8. doi: 10.1055/s-2006-925177.
In our previous study, we showed that prostaglandin F2alpha (PGF2alpha) stimulates vascular endothelial growth factor (VEGF) synthesis via activation of p44/p42 mitogen-activated protein (MAP) kinase via protein kinase C (PKC) in osteoblast-like MC3T3-E1 cells. In addition, we demonstrated that incadronate amplified, and tiludronate suppressed PGF2alpha-induced VEGF synthesis among bisphosphonates, while alendronate or etidronate had no effect. In the present study, we investigated the effects of minodronate, a newly developed bisphosphonate, on PGF (2alpha)-induced VEGF synthesis in MC3T3-E1 cells. Minodronate significantly reduced VEGF synthesis induced by PGF2alpha dose-dependently at levels between 3 and 100 microM. PGF2alpha-stimulated phosphorylation of Raf-1, MEK1/2 and p44/p42 MAP kinase were suppressed by minodronate. 12-O-tetradecanoylphorbol-13-acetate (TPA), a direct activator VEGF synthesis induced by PKC, was inhibited by minodronate. Minodronate inhibited Raf-1, MEK1/2 and p44/p42 MAP kinase phosphorylation induced by TPA. Mevalonate failed to affect the suppressive effect of minodronate on PGF2alpha-induced VEGF synthesis. Taken together, these results indicate that minodronate suppresses PGF2alpha-stimulated VEGF synthesis at the point between PKC and Raf-1 in osteoblasts.
在我们之前的研究中，我们发现前列腺素F2α（PGF2α）通过蛋白激酶C（PKC）激活p44/p42丝裂原活化蛋白（MAP）激酶，从而刺激成骨样MC3T3-E1细胞中血管内皮生长因子（VEGF）的合成。此外，我们证明了在双膦酸盐中，因卡膦酸盐增强而替鲁膦酸盐抑制PGF2α诱导的VEGF合成，而阿仑膦酸盐或依替膦酸盐则无此作用。在本研究中，我们研究了新开发的双膦酸盐米诺膦酸盐对MC3T3-E1细胞中PGF（2α）诱导的VEGF合成的影响。米诺膦酸盐在3至100微摩尔的浓度范围内，剂量依赖性地显著降低了PGF2α诱导的VEGF合成。米诺膦酸盐抑制了PGF2α刺激的Raf-1、MEK1/2和p44/p42 MAP激酶的磷酸化。12-O-十四烷酰佛波醇-13-乙酸酯（TPA）是PKC诱导的VEGF合成的直接激活剂，它被米诺膦酸盐抑制。米诺膦酸盐抑制了TPA诱导的Raf-1、MEK1/2和p44/p42 MAP激酶的磷酸化。甲羟戊酸未能影响米诺膦酸盐对PGF2α诱导的VEGF合成的抑制作用。综上所述，这些结果表明米诺膦酸盐在成骨细胞中PKC和Raf-1之间的位点抑制PGF2α刺激的VEGF合成。
